DESCRIPTION:(adapted from applicant's abstract) Hippocampal function is modulated by changing levels of the ovarian steroids, estradiol and progesterone, in adult females. Of particular interest here are the observations that 1) estradiol modulates long-term potentiation (LTP) and long-term depression (LTD) of the CA3-CA1 synapses and 2) estradiol increases the excitability of CAl pyramidal neurons. We hypothesize that these two observations are not independent and that the increased neuronal excitability underlies the estradiol-dependent changes in synaptic plasticity. Thus the long-term goal of this new R01 application is to understand how changing levels of estradiol modulate the excitability of the hippocampal CA1 region and thereby the long-term synaptic modification that occurs at the CA3-CA1 synapses. Here the focus of study is the hypothesis that estradiol increases recurrent CA 1-CA 1 connectivity. Using electrophysiological and pharmacological methods in hippocampal CA1 mini-slices from adult, ovariectomized (OVX) rats pretreated with estradiol or vehicle, Aim 1 characterizes the magnitude of this changed excitability and tests hypotheses concerning the proximal causes of this enhanced excitability. Aim 2 addresses the physiological significance of this enhanced excitability using CAl mini-slices from normally cycling rats across the estrous cycle. We will also determine whether the time course of the increase in excitability across the estrous cycle correlates with the time course of the changes of synaptic plasticity (LTP and LTD) at the CA3-CA 1 synapses. Aim 3 uses morphological methods to explore the hypothesis that this estradiol-dependent increase in the excitability of CAl pyramidal neurons involves the formation of recurrent excitatory CAl-CAl synapses. We will determine if the local axonal arborizations of CAl pyramids increase with estradiol treatment of OVX rats. Aim 4 tests the hypothesis that this estradiol-dependent increase in hippocampal excitability requires the action of genomic estrogen receptors. These studies will help us to understand better how estrogens modulate the hippocampal function and thus its cognitive functions in females. Moreover, these are likely to provide important insights for understanding the biological basis of memory problems that can occur with menopause.